CN102702051A - Preparation method of cilastatin sodium - Google Patents
Preparation method of cilastatin sodium Download PDFInfo
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- CN102702051A CN102702051A CN201110081611XA CN201110081611A CN102702051A CN 102702051 A CN102702051 A CN 102702051A CN 201110081611X A CN201110081611X A CN 201110081611XA CN 201110081611 A CN201110081611 A CN 201110081611A CN 102702051 A CN102702051 A CN 102702051A
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Abstract
The invention belongs to the field of pharmaceutical synthesis, and provides a preparation method of cilastatin sodium, and the method comprises the following steps: performing condensation, alkaline hydrolysis, and thioetherification of raw materials of 7-oxyhalogen alkyl heptylate and (s)-2,2-dimethylcyclopropane methanamide, adjusting the pH value of the thioetherified solution, washing by a nonpolar solvent, performing isomerization, purification by a neutral macroporous adsorption resin, and salt formation so as to obtain the cilastatin sodium solid. The invention reduces the generation of impurities, improves the isomerization efficiency, simplifies the preparation process, and effectively improves the yield and purity of cilastatin sodium.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to a kind of preparation method of cilastatin sodium.
Background technology
Cilastatin sodium (Cilastain Sodium Salt), chemistry is by name: (z)-and 7-[(2R)-(2-amino-2-carboxy ethyl) sulphur] [(1S)-2,2-dimethyl-cyclopropane carboxamide base]-2-heptenoic acid sodium, its chemical structural formula is following:
Cilastatin sodium can suppress the degraded of kidney dehydrogenation pepx to β-Nei Xiananleikangshengsu such as imipenum, increases the concentration of imipenum in the urinary tract, improves the activity of imipenum, reduces the renal toxicity of medicine, heightens the effect of a treatment.At present, imipenum/cilastatin composition of sodium is used widely as a kind of extensive pedigree antibiotic clinically.
At present the compound method of relevant cilastatin sodium bibliographical information is similar, all be by the halides of alpha-keto carboxylic acid earlier with (s)-2, the reaction of 2-dimethyl-cyclopropane carboxamide obtains after thioetherification again.Wherein the halides of alpha-keto carboxylic acid with (s)-2,2-dimethyl-cyclopropane carboxamide reaction obtains two kinds of isomer of Z/E, does not hope that the E isomer that obtains has 10-13% approximately.
Synthetic route:
For eliminating the influence of E isomer, patent W02006/022511, CN200710090592.0 are through the selective hydrolysis E isomer; Patent CN200710099332.X, CN200910155659.3 separate the Z/E isomer through crystallization processes, though this type of thinking has improved the purity of cilastatin sodium effectively, technology is loaded down with trivial details, equipment increases not suitability for mass industrialized production.
U.S. Pat 5147868 at pH=3, adds thermal isomerization under 85 ℃ of-90 ℃ of conditions with mixture, and this method simply is beneficial to industriallization, but because mixing solutions is complicated, the heating isomerization process can form the impurity of 5-8%, elimination process difficulty; Its purge process adopts Zeo-karb to carry out chromatography and removes inorganic salt, causes the degraded of cilastatin sodium in view of the ion exchange resin use has the heat release meeting, so the suitable use ion exchange resin of industriallization.
Patent CN02821284 is through changing isomerisation conditions (pH=0.5-1.5), and purification phase uses non-ionic adsorption resin to obtain more excellent result.Yet we are difficult to get a desired effect with cilastatin sodium yield and the purity that the method separation and purification of illustration among the patent CN02821284 obtains, and complex operation is still waiting better method and improves yield and purity to simplify to handle.
Summary of the invention
The present invention provides a kind of preparation method of cilastatin sodium; Transformation efficiency is low in the heating isomerization process that exists in the solution prior art, is prone to generate impurity, the technical problem that impurity is difficult to remove; The present invention is through the pH value of control thioetherification afterreaction liquid; And reaction solution carried out pre-treatment, and effectively solved the problem that exists in the prior art, have the effect that the purification with macroreticular resin process is simplified simultaneously; The yield and the purity of finished product cilastatin sodium are significantly improved, and the present invention is easy and simple to handle, be suitable for suitability for industrialized production.
Preparing method's step of cilastatin sodium of the present invention is following:
(1) with the 7-oxyhalogen for heptanoic alkyl ester with (s)-2, the 2-dimethyl-cyclopropane carboxamide is a raw material, it obtains mixing Z/E7-halogen-(2s)-2,2-dimethyl-cyclopropane carboxamide-2-heptenoic acid through condensation, alkaline hydrolysis;
(2) with Z/E7-halogen-(2s)-2,2-dimethyl-cyclopropane carboxamide-2-heptenoic acid and cysteine hydrochloride carry out thioetherification reaction under alkaline condition;
(3) it is acid thioetherification reaction liquid being transferred pH value, after the non-polar solvent washing, with water heating carrying out isomerization reaction;
(4) directly through neutral purification with macroreticular resin, elutriant obtains the cilastatin sodium solid through the aftertreatment salify to isomerization reaction liquid.
Particularly, step (1) condensation reaction, raw material 7-oxyhalogen can be selected for heptanoic alkyl ester: muriate, bromide; The alkyl ester of C1-C5, preferred 7-chlorine oxoheptanoate, 7-bromine oxoheptanoate, 7-chlorine oxo butyl heptylate; Reaction solvent is optional one of following: toluene, benzene, YLENE, preferred toluene; The preferred tosic acid of catalyzer; Preferred 110 ℃-130 ℃ of temperature of reaction; The 7-oxyhalogen for heptanoic alkyl ester with (s)-2, the molar feed ratio of 2-dimethyl-cyclopropane carboxamide preferred 1.0: 1.1-1.5; Catalyzer tosic acid dosage is the 1%-2% of 7-oxyhalogen for the heptanoic alkyl ester quality, and alkali is one or more in yellow soda ash, sodium hydroxide, Pottasium Hydroxide and the sodium hydride in the alkaline condition hydrolytic process, preferred sodium hydride or sodium hydroxide.
Step (2) thioetherification reaction is preferably carried out in sodium hydroxide solution, and Z/E7-halogen-(2s)-2,2-dimethyl-cyclopropane carboxamide-2-heptenoic acid and cysteine hydrochloride molar ratio are preferably 1.0: 1.1-1.2; Preferred 18 ℃-25 ℃ of temperature of reaction, preferred 12h-15h of reaction times.
Step (3) thioetherification reaction liquid transfers to the pH value and is 1.6-3.5, and preferred pH value is 1.8-2.4; The used acid of adjust pH is one or more mixtures in sulfuric acid, hydrochloric acid, nitric acid, the phosphoric acid, preferred hydrochloric acid; Said non-polar solvent is one or more mixing in ether, sherwood oil, ETHYLE ACETATE and the normal hexane; The heating isomerisation temperature is 90 ℃-95 ℃, and adding the thermal isomerization time is 0.5h-1.5h.
The said polymeric adsorbent of step (4) comprises polyacrylic ester or vinylbenzene and many vinyl benzenes multipolymer; Elutriant is respectively water and volume ratio is the methanol aqueous solution of 30%-50%.
Technique effect of the present invention is:
Through the pH value of control thioetherification afterreaction liquid, and reaction solution carried out pre-treatment, reduced the generation of impurity in the heating isomerization process, improved the efficient of isomerization process; Have the effect that neutral purification with macroreticular resin process is simplified simultaneously, use quantity of solvent to reduce, the yield and the purity of resulting cilastatin sodium obviously improve.
Embodiment
Further describe beneficial effect of the present invention through following examples at present; Be interpreted as these embodiment and only be used for the purpose of illustration; Do not limit the scope of the invention, conspicuous change and modification that while those of ordinary skills are made according to the present invention are also contained within the scope of the invention.
The preparation of embodiment 1 cilastatin sodium
Step (1) 25g7-chlorine oxoheptanoate, 13.68g (s)-2; 2-dimethyl-cyclopropane carboxamide and 0.14g tosic acid are dissolved in the toluene solution; 110 ℃ of conditions of temperature flow point water reaction next time 24h; Condensation is used Hydrogen chloride and bisulfite saturated aqueous solution of sodium washing reaction mixture respectively after accomplishing, and concentrates then to reclaim toluene.With dope hydrolysis reaction 12h in ethanol 20ml and 50% aqueous sodium hydroxide solution 25ml, regulate pH to 3.0～4.0, ETHYLE ACETATE 30ml extraction three times, the concentrated 31.2g dope that obtains with concentrated hydrochloric acid again.
Step (2) will go up and add 20g cysteine hydrochloride, 2N sodium hydroxide solution 120ml in the step dope, stirring at room reaction 12h under nitrogen protection;
Step (3) is used hydrochloric acid conditioning solution pH=1.5, and 50ml ether washing three times is warming up to 93 ℃, again insulation reaction 0.5h;
Step (4) is reduced to room temperature with step (3) gained reaction soln; Regulate PH to 3.0 with 2N Na0H solution; Last appearance is to the adsorption column that Bayer VP 0C 1064 polymeric adsorbents are housed; Remove inorganic salt and water-soluble impurity with the purified water washing, use methanol aqueous solution wash-out product then, collect straight product post component and concentrate.Products obtained therefrom is dissolved in 316ml water; Regulate PH to 7.0 with the 2N sodium hydroxide solution, 40 ℃ remove solvent under reduced pressure, add the 150ml dissolve with methanol; Drip 1000ml acetone to separating out a large amount of solids; Suction filtration, vacuum-drying below 40 ℃ get 31.6g white powder solid cilastatin sodium (molar yield 68.6%, HPLC measures purity 99.2%).
The preparation of embodiment 2 cilastatin sodiums
Step (1) is used the dean-stark water trap; 20g7-bromine oxoheptanoate, 12g (s)-2; 2-dimethyl-cyclopropane carboxamide and 0.2g tosic acid are dissolved in 120 ℃ of conditions of toluene solution flow point water reaction next time 24h; Condensation is used Hydrogen chloride and bisulfite saturated aqueous solution of sodium washing reaction mixture respectively after accomplishing, and concentrates then to reclaim toluene.With dope hydrolysis reaction 8h in 15ml ethanol and 30% aqueous sodium carbonate 50ml, regulate pH to 3.0～4.0, ETHYLE ACETATE 25ml extraction 2 times, the concentrated 22.8g dope that obtains with concentrated hydrochloric acid.
Step (2) will go up step dope, 15g cysteine hydrochloride stirring and dissolving in 100ml water, 20ml ethanol, and Dropwise 5 0% sodium hydroxide solution 20ml is in stirring at room reaction 14h;
Step (3) is used hydrochloric acid conditioning solution pH=2.4, and 30ml ETHYLE ACETATE washing 3 times is warming up to 95 ℃, again insulation reaction 1.5h;
Step (4) is reduced to room temperature with step (3) gained reaction soln, directly goes up appearance to the adsorption column that Bayer vp oc1064 polymeric adsorbent is housed, and washs to the no Cl of Silver Nitrate detection with purified water
-, use 1L 40% methanol aqueous solution wash-out product then, collect straight product post component and concentrate.Products obtained therefrom is dissolved in 150ml methyl alcohol; The ethanolic soln of dropping sodium (5.4gNaOH/150ml ethanol); Drip to finish and stir 30min, drip 1000ml acetone to separating out a large amount of solids, suction filtration; Vacuum-drying below 40 ℃ gets 20.8g white powder solid cilastatin sodium (molar yield 68.5%, HPLC measures purity 99.1%).
Embodiment 3
Step (1) 15g7-chlorine oxoheptanoate, 8.2g (s)-2; 2-dimethyl-cyclopropane carboxamide and 0.25g tosic acid are dissolved in the xylene solution; The flow point water reaction next time of 130 ℃ of conditions of temperature; Condensation is used Hydrogen chloride and bisulfite saturated aqueous solution of sodium washing reaction mixture respectively after accomplishing, and concentrates then to reclaim YLENE.With dope hydrolysis in 15ml ethanol and 15ml 50% sodium hydroxide solution, regulate pH to 3～4, ETHYLE ACETATE 20ml extraction 2 times, the concentrated 19.8g dope that obtains through the 2N hydrochloric acid soln.
Step (2) will go up and add 12g cysteine hydrochloride, 2N sodium hydroxide solution 80ml in the step dope, in stirring at room reaction 13h;
Step (3) is used hydrochloric acid conditioning solution pH=2.0, and 50ml petroleum ether 3 times is warming up to 90 ℃, again insulation reaction 1h;
Step (4) is reduced to room temperature with step (3) gained reaction soln, directly goes up appearance to the adsorption column that the HP-20 polymeric adsorbent is housed, and removes inorganic salt and water-soluble impurity with the purified water washing, uses 40% methanol aqueous solution wash-out product then, collects straight product post component and concentrates.Products obtained therefrom is dissolved in 100ml methyl alcohol; Use the 2N sodium hydroxide solution to regulate pH to 7.0; Drip to finish and stir 30min, drip the 1000ml ether to separating out a large amount of solids, suction filtration; Vacuum-drying below 40 ℃ gets 18.9g white powder solid cilastatin sodium (molar yield 68.4%, HPLC measures purity 99.0%).
Claims (11)
1. the preparation method of a cilastatin sodium may further comprise the steps:
(1) with the 7-oxyhalogen for heptanoic alkyl ester with (s)-2, the 2-dimethyl-cyclopropane carboxamide is a raw material, it obtains mixing Z/E7-halogen-(2s)-2,2-dimethyl-cyclopropane carboxamide-2-heptenoic acid through condensation, alkaline hydrolysis;
(2) with Z/E7-halogen-(2s)-2,2-dimethyl-cyclopropane carboxamide-2-heptenoic acid and cysteine hydrochloride carry out thioetherification reaction under alkaline condition;
(3) be acid with thioetherification reaction liquid adjust pH, after the non-polar solvent washing, with water heating carrying out isomerization reaction;
(4) isomerization reaction liquid is collected the feed liquid salify and is obtained the cilastatin sodium solid directly through neutral purification with macroreticular resin.
2. the preparation method of cilastatin sodium as claimed in claim 1 is characterized in that 7-oxyhalogen in the step (1) is a kind of in 7-chlorine oxoheptanoate, 7-bromine oxoheptanoate or the 7-chlorine oxo butyl heptylate for heptanoic alkyl ester.
3. the preparation method of cilastatin sodium as claimed in claim 1 is characterized in that in the step (1) with tosic acid as catalyzer.
4. the preparation method of cilastatin sodium as claimed in claim 1 is characterized in that the used alkali of hydrolysis is carbon in the step (1)
In acid sodium, sodium hydroxide, Pottasium Hydroxide and the sodium hydride one or more.
5. the preparation method of cilastatin sodium as claimed in claim 1 is characterized in that adjust pH is 1.6-3.5 in the step (3).
6. like the preparation method of claim 1 or 5 described cilastatin sodiums, it is characterized in that adjust pH is 1.8-2.4 in the step (3).
7. the preparation method of cilastatin sodium as claimed in claim 1 is characterized in that the described non-polar solvent of step (3) is one or more in ether, sherwood oil, ETHYLE ACETATE and the normal hexane.
8. the preparation method of cilastatin sodium as claimed in claim 1 is characterized in that the heating isomerisation temperature is 90 ℃-95 ℃ in the step (3).
9. the preparation method of cilastatin sodium as claimed in claim 1, it is characterized in that adding in the step (3) the thermal isomerization time is 0.5 hour-1.5 hours.
10. the preparation method of cilastatin sodium as claimed in claim 1 is characterized in that the described neutral macroporous adsorbent resin of step (4) is polyacrylic ester or vinylbenzene and many vinyl benzenes multipolymer.
11. the preparation method of cilastatin sodium as claimed in claim 1 is characterized in that the neutral purification with macroreticular resin elutriant of step (4) is respectively water and volume ratio is the methanol aqueous solution of 30%-50%.
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| CN201110081611.XA CN102702051B (en) | 2011-03-26 | 2011-03-26 | A kind of preparation method of cilastatin sodium |
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| CN201110081611.XA CN102702051B (en) | 2011-03-26 | 2011-03-26 | A kind of preparation method of cilastatin sodium |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109111381A (en) * | 2018-10-30 | 2019-01-01 | 雅本化学股份有限公司 | A kind of preparation method of cilastatin |
| CN110305033A (en) * | 2018-03-20 | 2019-10-08 | 鲁南制药集团股份有限公司 | A kind of purification process of cilastatin sodium intermediate |
| CN115260067A (en) * | 2022-08-26 | 2022-11-01 | 同舟纵横（厦门）流体技术有限公司 | Method for purifying cilastatin mother liquor |
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| US5147868A (en) * | 1978-07-24 | 1992-09-15 | Merck & Co., Inc. | Thienamycin renal peptidase inhibitors |
| WO2003018544A1 (en) * | 2001-08-24 | 2003-03-06 | Ranbaxy Laboratories Limited | Process for the preparation of cilastatin |
| WO2006022511A1 (en) * | 2004-08-25 | 2006-03-02 | Dong Kook Pharm. Co., Ltd. | Novel process for the preparation of cilastatin sodium salt |
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| CN101307015A (en) * | 2007-05-16 | 2008-11-19 | 深圳市海滨制药有限公司 | Process for preparing cilastatin sodium |
| CN101386588A (en) * | 2008-08-28 | 2009-03-18 | 珠海联邦制药股份有限公司 | Method for preparing cilastatin acid |
| CN101792410A (en) * | 2009-12-29 | 2010-08-04 | 浙江工业大学 | Preparation method of cilastatin sodium |
| CN101851186A (en) * | 2010-05-31 | 2010-10-06 | 浙江师范大学 | Method for synthesizing cilastatin sodium |
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2011
- 2011-03-26 CN CN201110081611.XA patent/CN102702051B/en active Active
Patent Citations (8)
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| US5147868A (en) * | 1978-07-24 | 1992-09-15 | Merck & Co., Inc. | Thienamycin renal peptidase inhibitors |
| WO2003018544A1 (en) * | 2001-08-24 | 2003-03-06 | Ranbaxy Laboratories Limited | Process for the preparation of cilastatin |
| WO2006022511A1 (en) * | 2004-08-25 | 2006-03-02 | Dong Kook Pharm. Co., Ltd. | Novel process for the preparation of cilastatin sodium salt |
| CN101200434A (en) * | 2006-12-11 | 2008-06-18 | 维思凯有限公司 | Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid |
| CN101307015A (en) * | 2007-05-16 | 2008-11-19 | 深圳市海滨制药有限公司 | Process for preparing cilastatin sodium |
| CN101386588A (en) * | 2008-08-28 | 2009-03-18 | 珠海联邦制药股份有限公司 | Method for preparing cilastatin acid |
| CN101792410A (en) * | 2009-12-29 | 2010-08-04 | 浙江工业大学 | Preparation method of cilastatin sodium |
| CN101851186A (en) * | 2010-05-31 | 2010-10-06 | 浙江师范大学 | Method for synthesizing cilastatin sodium |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305033A (en) * | 2018-03-20 | 2019-10-08 | 鲁南制药集团股份有限公司 | A kind of purification process of cilastatin sodium intermediate |
| CN109111381A (en) * | 2018-10-30 | 2019-01-01 | 雅本化学股份有限公司 | A kind of preparation method of cilastatin |
| CN115260067A (en) * | 2022-08-26 | 2022-11-01 | 同舟纵横（厦门）流体技术有限公司 | Method for purifying cilastatin mother liquor |
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